Sep 23 2022
This tutorial will take you through the basics of protein modeling. Topics include:
ICM has an excellent record in building accurate models by homology. The ICM modeling procedure builds the framework, shakes up the side-chains and loops by global energy optimization. You can also color the model by local reliability to identify the potentially incorrect regions of the model. ICM also offers a fast and completely automated method to build a model by homology and extract the best fitting loops from a database of all known loops. It just takes a few seconds to build a complete model by homology with loops. Some selected publications related to modeling and structure determination are listed here.
Abagyan, R.A., and Totrov, M.M. (1994). Biased Probability Monte Carlo Conformational Searches and Electrostatic Calculations for Peptides and Proteins. J. Mol. Biol., 235, 983-1002
Cardozo, T., Totrov, M., and Abagyan, R. (1995). Homology modeling by the ICM method. Proteins: Structure, Function, Genetics, 23, 403-414
Abagyan, R., and Totrov, M. (1999). Ab initio folding of peptides by the optimal-bias Monte Carlo minimization procedure. Journal of Computational Physics, 151, 402-421
Maiorov, V.N., and Abagyan, R.A. (1997). A new method for modeling large-scale rearrangements of protein domains. Proteins, 27, 410-424
Schapira, M., Totrov, M. and Abagyan, R. (2002). Structural Model of Nicotinic Acetylcholine Receptor Isotypes Bound to cetylcholine and Nicotine. BMC Structural Biology 2:1
In this example we will build a homology model of GPR120 which is a member of the Class A GPCRs. GPR120 is gaining particular interest because it has been shown to be involved in the insulin-sensitizing effects of omega 3 fatty acids as well as inflammation. GPR120 dysfunction is responsible for reduced fat metabolism, thereby leading to obesity.
In this example we will use the high precision loop modeling method Arnautova et al Proteins. 2010, 79:477 to model a loop region in Anthrax Protective Antigen which contains a proline residue where the cis/trans conformation is not clear from the available X-ray crystal structures. We will determine the most energetically favorable conformation of the proline and the neighboring loop residues.
The effect of mutation on protein binding can be predicted.
In this example the effect of mutation on binding between chymotrypsin and an inhibitor is predicted (using PDB 1CBW). LYS15 in the inhibitor makes a key binding interaction with the protease and mutation to alanine leads to a significant drop in the binding free energy.
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The effect of mutation on protein stability can be predicted. In this example we mutate residue F26 to Ala in the crystal structure of bovine Acyl-CoA binding protein. The experimentally calculated value of this mutation is 1.54 kcal/mol ( Kragelund et al. NSB 6, 594:601 (1999) ) .
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